Note: Descriptions are shown in the official language in which they were submitted.
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~OMPOSITiON AND METHOD FOR TREATING ALLERGIC
DISEASES
FIELD OF THE INVENTION
The present invention generally relates to compositions and methods
for treating allergic rhinitis and other respiratory diseases. It specifically
discloses compositions which comprise combinations of antagonists of
neurokinin receptors and antagonists of histamine receptors, and methods
for treating the above-noted diseases with such compositions.
BACKGROUND OF THE INVENTION
Neurokinin receptors such as the NK, and the NK2 receptors are
found in the central nervous system, the circulatory system, and the
peripheral tissues of mammals, and are involved in a variety of biological
processes. Antagonists of the neurokinin receptors are, therefore, expected
to be useful in the treatment or prevention of various mammalian diseases
such as, for example, pulmonary disorders such as asthma, cough,
bronchospasm, chronic obstructive pulmonary diseases, and airway
hyperactivity; skin disorders and itch, for example, atopic dermatitis, and
cutaneous wheat and flare; neurogenic inflammatory diseases such as,
arthritis, migraine, nociception; CNS diseases such as anxiety, emesis,
Parkinson's disease, movement disorders and psychosis; convulsive
disorders, renal disorders, urinary incontinence, ocular inflammation"
inflammatory pain, and eating disorders such as food intake inhibition;
allergic rhinitis, neurodegenerative disorders, psoriasis, Huntington's
disease, depression and various disorders such as Crohn's disease. NK,
receptors have been reported to be involved in microvascular leakage and
mucus secretion, and NK2 receptors have been associated with smooth
muscle contraction, making NK, and NK2 receptor antagonists especially
useful in the treatment and prevention of asthma. NK, and NK2 receptor
antagonists have been reported such as, for example, in U.S. patents
5,798,359; 5,795,894; 5,789,422; 5,783,579; 5,719,156; 5,696,267;
5,691,362; 5,688,960; 5,654,316; and in "Recent Advances in Neurokinin
Receptor Antagonists", by C. J. Ohnmacht Jr., et al, Annual Reports in
Medicinal Chemistry, A. M. Doherty Ed., 33, 71-80 (1998).
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and related disorders is well known. A discussion is provided by, for
example, R. Aslanian et al, Exp.Opin.Ther.Patents, 7~~., 201-207 (1997) as
well as in references cited therein.
The discovery of the H3 receptor is a fairly recent phenomenon. The
H3 receptor is most abundantly distributed in the CNS, and in lesser
amounts in peripheral tissues. The H3 receptor is considered an important
general neuroregulatory mechanism for various physiological processes,
not only in the CNS but in peripheral tissues as well. A discussion of the H3
receptor and antagonists therefor can be found in J. G. Phillips et al, Annual
Reports in Medicinal Chemistry, J. Bristol, ed., ~, 31-40 (1998).
Compounds that antagonize both the NK, and H, receptors are
disclosed, for example, in WO 96-06094 (Marion Merrell Dow, 1996). Dual
antagonists of the H, and H3 receptors are discussed, for example, in
pending U.S. patent application, Serial No. 08/909,319, filed August 14,
1997. Pending U.S. patent application, Serial No. 60/068,638, filed
December 23, 1997, discloses compositions comprising leukotriene
antagonists and H, receptors.
It would be highly desirable to enhance the efficacy of the neurokinin
antagonists to improve their overall efficacy.
SUMMARY OF THE INVENTION
The afore-mentioned objective and other objectives and desires are
addressed by the present invention which, in one embodiment, provides a
composition for treating and preventing allergic rhinitis and other
respiratory
diseases such asthma, cough, wheezing and the like. The inventive
composition comprises: (i) a therapeutically effective amount of at least one
neurokinin antagonist; (ii) a therapeutically effective amount of at least one
H3 antagonist and (iii) a therapeutically effective amount of at feast one H,
antagonist. One or more of the antagonists may be substituted by a
pharmaceutically acceptable derivative such as salt, ester, and the like, if
so
desired. Optionally, the composition may additionally contain a
pharmaceutically acceptable carrier, a decongestant (such as, for example,
pseudoephedrine), a cough suppressant (such as, for example,
dexrtomethorphan), expectorant (such as, for example, guaifenesin),
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analgesics (such as, for example, aspirin, ibuprofen and acetaminophen) or
mixtures thereof.
Generally, the amount of the neurokinin antagonist content in the
inventive composition is about 1-1,000 milligrams, preferably about 10-500
milligrams, and typically about 50-200 milligrams. The amount of the H3
antagonist is generally about 1-1,000 milligrams, preferably about 1-500
milligrams, and typically about 1-50 milligrams. The amount of the H,
antagonist is generally about 1-200 milligrams, preferably about 1-100
milligrams, and typically about 2-10 milligrams.
The invention further provides a method for treating asthma and
allergic disorders, sneezing, itching runny nose, nasal congestion, redness
of the eye, tearing, itching of the ears or palate, sinusitis, and coughs
associated with postnasal drip symptoms in a mammalian organism in need
of such treatment comprising administering a pharmaceutical composition
as described above.
DETAILED DESrRIPTION OF THE INVENTION
In one embodiment, the present invention discloses pharmaceutical
compositions that are useful in treating and preventing allergic rhinitis,
asthma and related disorders. The composition comprises, in combination, a
therapeutically effective amount of at least one neurokinin antagonist, a
therapeutically effective amount of at least one H3 antagonist and a
therapeutically effective amount of at least one H, antagonist. One or more of
the antagonists may be substituted by a pharmaceutically acceptable
derivative such as salt (such as, for example, hydrochloride), ester, and the
like.
Several neurokinin antagonists that are currently known are useful in
the practice of the present invention. Non-limiting examples of such useful
neurokinin antagonists include, for example, those belonging to the
chemical class of oximes, hydrazones, piperidines, piperazines, aryl alkyl
amines, hydrazones, nitroalkanes, amides, isoxazolines, quinolines,
isoquinofines, azanorbornanes, naphthyridines, benzodiazepines and the
like. Many are disclosed in the U.S. patents cited earlier in this patent
application. Preferred NK antagonists are those disclosed in the above-
noted U.S. patents 5,798,359; 5,795,894; 5,789,422; 5,783,579; 5,719,156;
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5,696,267; 5,691,362; 5,688,960; 5,654,316. The general formula of some of
so-disclosed compounds is:
A
Z X T
a
Q
wherein Z is
0
B Y' m
\ ' or N N
N
where B is OR2; NRsCOR2, CONR6R, or NR2CONRER,,
m=Oorl,
P is R5 aryl; or RS heteroaryl; and
Y is H, CR2R3C02R6; CR2R3CONR6R, or CR2R3NR6COR2;
a= b= 0, 1 or 2;
Q has the same definitions as P above, with the proviso that P and Q may be
the same or different;
A is =N-OR,; =N-NR2R3; or =CR, R2;
X is -O-; -NRs ; -N(R6)CO-; or -CO-NRs ;
T is R4 aryl; R4-heteroaryl; R~-cycloalkyl; or R2-bridged cycloalkyi;
R, is H, C,-Cs alkyl; or (CHZ)~-G where n=1-6,
G iS H; R4 aryl; R4-heteroaryl; CORE; C02R6; CONR6R,; CN; OCOR6; S03R2;
C(=NORZ)NRsR,; C(=NR2)NR6R,, with the proviso that when nil, G can
additionally be OR6, NR fiR, or NR6(CO)R,;
R2 and R3 are independently H or C,-C6 alkyl;
R4 and R5 are independently 1, 2 or 3 substituents independently selected
from OR2, OC(O)R2, OC(O)NR6R,, C,-Cs alkyl, H, halogen, CF3, CZF5, or OCF3;
and
Rs and R, are independently selected from H or C,-C6 alkyl, with the proviso
that when R6 and R, are part of NRsR, then said NR6R, may form part of a C5
C6 ring wherein 0-2 ring members are selected from the group consisting of -
O-, -S- and -NR2 , with the further proviso that said CS C6 ring may contain
substituents on said ring with said substituents being selected from the
group consisting of hydrogen, halogen, -ORs and -COOR6.
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Particularly preferred neurokinin antagonists are those disclosed in
the above-mentioned U.S. patents and belonging to the general formula:
CH3
('O
N
R ~ N
O N CI
C
O
CI
and stereoisomers thereof. More particularly preferred are the stereolsomers
with the general formula:
IH3 CI
O
N
N
R,
N
O N \ CI
CI
where R is H, CH2CONH2, CH2CONHMe, CHZCONMe2 or
H O N OH
2
The currently known H3 receptor antagonists cannot be easily
classified chemically. Illustrative H3 receptor antagonists useful in the
practice of the present invention include, without limitation, thioperamide
(technical name: N-cyclohexyl-4-(1H-imidazol-4-yl)-1-
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piperidinecarbothioamide, CAS Registry Number: 106243-16-7),
impromidine (technical name: N-[3-(1 H-imidazol-4-yl)propyl]-N'-[2-[[(5-
methyl-1 H-imidazol-4-yl)methyl]thio]ethyl]guanidine, CAS Registry Number:
65573-02-6), burimamide (technical name: N-[4-(1 H-imidazol-4-yl}butyl]-N'-
methylthiourea, CAS Registry Number: 55720-27-9), clobenpropit (technical
name: [(4-chlorophenyl)methyl]-3-(1 H-imidazol-4-yl)propyl ester of
carbamimidothioic acid, CAS Registry Number: 145231-45-4), impentamine,
mifetidine, S-sopromidine (technical name: N-(2-(1 H-imidazol-4-yl}-1-
methylethyl]-N'-[2-[[(5-methyl-1 H-imidazol-4-yl}methyl]thio]ethylguanidine,
CAS Registry Number: 99616-14-5), R-sopromidine (CAS Registry Number:
79313-75-0), SKF-91486 (technical name: [3-(1 H-imidazol-4-
yl)propylguanidine, CAS Registry Number: 46129-28-6), GR-175737 (CAS
Registry Number: 203874-78-6), GT-2016 (CAS Registry Number: 152241-
24-2), GT-2331, UCL-1199 (technical name: 2-[[2-(1 H-imidazol-4-
yl)ethyl]thio]-5-nitropyridine, CAS Registry Number: 152030-16-5), 1 H-
imidazole-4-pentanamine (CAS Registry Number: 34973-91-6), clozapine
(technical name: 8-chloro-11-(4-methyl-1-piperazinyl)-5H-
dibenzo[b,e][1,4]diazepine, CAS Registry Number: 54241-01-9) and the
compound N-(3,5-dichlorophenyl)-N'-[[4-[(1 H-imidazol-
4-yl)methyl]phenyl]methyl]urea, and whose structure is shown below:
H N
N
HN~ I
N
O
CI
Certain benzamidines and benzylamidines as H3 antagonists have been
described by R. Aslanian ef al, Bioorganic & Medicinal Chemistry, $, 2263-
2268 (1998). Other compounds can readily be evaluated to determine
activity at H3 receptors by known methods, including, for example, the
guinea pig brain membrane assay and the guinea pig neuronal ileum
contraction assay, both of which are described in U.S. patent 5,352,707.
Another useful assay utilizes rat brain membranes and is described by West
et al, "Identification of Two H3-Histamine Receptor Subtypes", Molecular
Pharmacology, ~, 610-613 (1990).
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Numerous chemical substances are known to have histamine H,
receptor antagonist activity. Many such compounds can be classified
broadly as ethanolamines, ethylenediamines, alkylamines, phenothiazines,
piperidines, and the like. Illustrative H, receptor antagonists useful in the
practice of the present invention include, without limitation, astemizole,
ceterizine, azatadine, azelastine, acrivastine, brompheniramine,
chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine,
carbinoxamine, descarboethoxyloratadine (also known as desloratadine or
"DCL" ), doxylamine, dimethindene, ebastine, epinastine, efletirizine,.
fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine,
mizolastine, mequitazine, mianserin, noberastine, norastemizole,
normethylastemizole, picumast, pyrilamine, promethazine, terfenadine,
tripelennamine, temelastine, trimeprazine, and tripolidine. Other compounds
can readily be evaluated to determine activity at H, receptors by known
methods including, for example, specific blockade of the contractile
response to histamine of isolated guinea pig ileum.
In a further embodiment, this invention discloses a method for
treatment of asthma, allergic rhinitis, and other allergic disorders,
sneezing,
itching runny nose, nasal congestion, redness of the eye, tearing, itching of
the ears or palate, wheezing, sinusitis, and coughs associated with
postnasal drip symptoms in a mammalian organism in need of such
treatment comprising administering a pharmaceutical composition which
comprises the neurokinin antagonist, H3 antagonist and the H, antagonist as
described above.
In the pharmaceutical compositions and methods of the present
invention, the active ingredients will typically be administered in admixture
with suitable pharmaceutical diluents, excipients or carriers (collectively
referred to herein as carrier materials) suitably selected with respect to the
intended form of administration, i.e. oral tablets, capsules (either solid-
filled,
semi-solid filled or liquid filled), powders for constitution, oral gels,
elixirs,
dispersible granules, syrups, suspensions, and the like, and consistent with
conventional pharmaceutical practices. For example, for oral administration
in the form of tablets or capsules, the active drug component may be
combined with any oral non-toxic pharmaceutically acceptable inert carrier,
such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium
phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and
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the like. Moreover, when desired or needed, suitable binders, lubricants,
disintegrating agents and coloring agents may also be incorporated in the
mixture. Powders and tablets may be comprised of from about 5 to about 95
percent inventive composition. Suitable binders include starch, gelatin,
natural sugars, com sweeteners, natural and synthetic gums such as acacia,
sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
Among the lubricants there may be mentioned for use in these dosage
forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and
the like. Disintegrants include starch, methylcellulose, guar gum and the
like.
Sweetening and flavoring agents and preservatives may also be included
where appropriate. Some of the terms noted above, namely disintegrants,
diluents, lubricants, binders and the like, are discussed in more detail
below.
Additionally, the compositions of the present invention may be
formulated in sustained release form to provide the rate controlled release of
any one or more of the components or active ingredients to optimize the
therapeutic effects, i.e. neurokinin antagonism, antihistaminic activity and
the
like. Suitable dosage forms for sustained release include layered tablets
containing layers of varying disintegration rates or controlled release
polymeric matrices impregnated with the active components and shaped in
tablet form or capsules containing such impregnated or encapsulated
porous polymeric matrices.
Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injections or addition of sweeteners and
opacifiers for oral solutions, suspensions and emulsions. Liquid form
preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions
and solids in powder form, which may be in combination with a
pharmaceutically acceptable carrier such as inert compressed gas, e.g.
nitrogen.
For preparing suppositories, a low melting wax such as a mixture of
fatty acid glycerides such as cocoa butter is first melted, and the active
ingredient is dispersed homogeneously therein by stirring or similar mixing.
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The molten homogeneous mixture is then poured into convenient sized
molds, allowed to cool and thereby solidify.
Also included solid form preparations which are intended to be
converted, shortly before use, to liquid form preparations for either oral or
parenteral administration. Such liquid forms include solutions, suspensions
and emulsions.
The compounds of the invention may also be deliverable ,
transdermally. The transdermal compositions may take the form of creams,
lotions, aerosols and/or emulsions and can be included in a transdermal
patch of the matrix or reservoir type as a re conventional in the art for this
purpose.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In
such form, the preparation is subdivided into suitably sized unit doses
containing appropriate quantities of the active components, e.g., an effective
amount to achieve the desired purpose.
The quantity of the inventive active composition in a unit dose of
preparation may be generally varied or adjusted from about 0.01 milligrams
to about 1,000 milligrams, preferably from about 0.01 to about 750
milligrams, more preferably from about 0.01 to about 500 milligrams, and
typically from about 0.01 to about 250 milligrams, according to the particular
application. The actual dosage employed may be varied depending upon
the patient's age, sex, weight and severity of the condition being treated.
Such techniques are well known to those skilled in the art. Generally, the
human oral dosage form containing the active ingredients can be
administered 1 or 2 times per day. The amount and frequency of the
administration will be regulated according to the judgment of the attending
clinician. A generally recommended daily dosage regimen for oral
administration may range from about 0.04 milligrams to about 4,000
milligrams per day, in single or divided doses.
Capsule - refers to a special container or enclosure made of methyl
cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or
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containing compositions comprising the active ingredients. Hard shell
capsules are typically made of blends of relatively high gel strength bone
and pork skin gelatins. The capsule itself may contain small amounts of
dyes, opaquing agents, plasticizers and preservatives.
Tablet- refers to a compressed or molded solid dosage form
containing the active ingredients with suitable diluents. The tablet can be
prepared by compression of mixtures or granulations obtained by wet
granulation, dry granulation or by compaction. .
Oral gels-refers to the active ingredients dispersed or solubilized in a
hydrophillic semi-solid matrix.
Powders for constitution refers to powder blends containing the active
ingredients and suitable diluents which can be suspended in water or juices.
Difuent - refers to substances that usually make up the major portion
of the composition or dosage form. Suitable diluents include sugars such as
lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn
rice and potato; and celluloses such as microcrystalline cellulose. The
amount of diluent in the composition can range from about 10 to about 90%
by weight of the total composition, preferably from about 25 to about 75%,
more preferably from about 30 to about 60% by weight, even more
preferably from about 12 to about 60%.
Disintegrants - refers to materials added to the composition to help it
break apart (disintegrate) and release the medicaments. Suitable
disintegrants include starches; ucold water soluble" modified starches such
as sodium carboxymethyl starch; natural and synthetic gums such as locust
bean, karaya, guar, tragacanth and agar; cellulose derivatives such as
methylcellulose and sodium carboxymethylcellulose; microcrystalline
celfuloses and cross-linked microcrystalline celluloses such as sodium
croscarmellose; alginates such as alginic acid and sodium alginate; clays
such as bentonites; and effervescent mixtures. The amount of disintegrant in
the composition can range from about 2 to about 15% by weight of the
composition, more preferably from about 4 to about 10% by weight.
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Binders - refers to substances that bind or "glue" powders together
and make them cohesive by forming granules, thus serving as the
"adhesive" in the formulation. Binders add cohesive strength already
available in the difuent or bulking agent. Suitable binders include sugars
such as sucrose; starches derived from wheat, com rice and potato; natural
gums such as acacia, gelatin and tragacanth; derivatives of seaweed such
as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic
materials such as methylcellulose and sodium carboxymethylcellulose and
hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as
magnesium aluminum silicate. The amount of binder in the composition can
range from about 2 to about 20% by weight of the composition, more
preferably from about 3 to about 10% by weight, even more preferably from
about 3 to about 6% by weight.
Lubricant - refers to a substance added to the dosage form to enable
the tablet, granules, etc. after it has been compressed, to release from the
mold or die by reducing friction or wear. Suitable lubricants include metallic
stearates such as magnesium stearate, calcium stearate or potassium
stearate; stearic acid; high melting point waxes; and water soluble lubricants
such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate,
polyethylene glycols and d'I-leucine. Lubricants are usually added at the
very last step before compression, since they must be present on the
surfaces of the granules and in between them and the parts of the tablet
press. The amount of lubricant in the composition can range from about 0.2
to about 5% by weight of the composition, preferably from about 0.5 to about
2%, more preferably from about 0.3 to about 1.5% by weight.
Glidents - materials that prevent caking and improve the flow
characteristics of granulations, so that flow is smooth and uniform. Suitable
glidents include silicon dioxide and talc. The amount of glident in the
composition can range from about 0.1 % to about 5% by weight of the total
composition, preferably from about 0.5 to about 2% by weight.
Coloring agents - excipients that provide coloration to the composition
or the dosage form. Such excipients can include food grade dyes and food
grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum
oxide. The amount of the coloring agent can vary from about 0.1 to about 5%
by weight of the composition, preferably from about 0.1 to about 1%.
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Bioavailability - refers to the rate and extent to which the active drug
ingredient or therapeutic moiety is absorbed into the systemic circulation
from an administered dosage form as compared to a standard or control.
Conventional methods for preparing tablets are known. Such
methods include dry methods such as direct compression and compression
of granulation produced by compaction, or wet methods or other special
procedures. Conventional methods for making other forms for administration
such as, for example, capsules, suppositories and the like are also well
known.
It will be apparent to those skilled in the art that many modifications,
variations and alterations to the present disclosure, both to materials and
methods, may be practiced. Such modifications, variations and alterations
are intended to be within the spirit and scope of the present invention.
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